Known in the art are a great number of chemical compounds exhibiting antiblastic activity, including 5-nitrofuran derivatives.
First reports on antitumor activity of compounds of the nitrofuran series are associated with nitrofurazone (furacin) [Green M. N., Firedgood Ch.E.- "Proc. Soc. Exp. Biol. N.Y.; 1948, v. 69, p. 603-604; Vasilieva V. A., Tutkevich L. M.- "Izv. AN. Latv. SSR, 1950, v. 37, pp. 57-64 (in Russian); Tutkevich L. M. - in the book "Furacin and Application Experience" (in Russian). Riga. 1953, pp. 175-180; Prior J. T., Ferguson J. H. - "Cancer (Philad.)". 1950. v. 3. pp. 1062-1072; Friedgood Ch., Green M. N. - "Cancer Res.". "Cancer Res.". 1950, v. 10. pp. 613-615] and with nitrofurfurylidene propane dinitryl [Petrakis N. L., Bierman H. R., Shimkin M. B.-"Cancer Res.". 1952. v. 12. p. 573; Gal E. M., Creenberg D. M.- "J. Am. Chem. Soc.". 1951. v. 73. pp. 502-503]. Later on, nitrofurazone was used for treating testicular tumors, mainly seminoma and its metastases [Friedgood Ch. E., Danza A. L., Boccabella A.- "Cancer Res." 1952. v. 12. pp. 262-263; Wildermuth O.- "Radiology". 1955. v. 65. pp. 599-603; I. Shiyama K. G., Adachi J- "Cancer Chemother. Abstr."1964. v. 5. pp. 439-440; Karol H. J.-"J. Urol (Baltimore)". 1960. v. 84. pp. 120-122; Hayllar B. L., O'Neal A. H. Dotterer J. A.- "J. Urol (Baltimore),". 1960. v. 84. pp. 565-568]. The data of clinical observations have given scientists an impetus to search for new nitrofuran derivatives exhibiting a stronger antitumor acitivity and less pronounced toxicity, and to study the role of various substitutes in the molecule of such compounds in antitumor activity thereof [Saidela F., Roye R., Bizany E. et al.- "Proceedings of the 8th International Anticancer Congress". v. 6.M., 1962, pp. 119-121].
During investigations into antitumor activity of nitrofuran derivatives it has been found that 5-nitrofuran decelerates the growth of Jensen sarcoma and Walker carcinosarcoma by 39-51%. 5-nitrofurfural, its vinylogs and acetals exhibit about the same activity and a higher acute toxicity. An antiblastic effect is caused by products of condensation of aldehydes of the nitrofuran series with (.beta.-hydrazinoethyl)pyridine, 3-hydrazino-4-amino-1,2,4-triazole [Giller S. A., Kalnberga R. Yu., Zidermane A. A. et al. In the book "Methods of Synthesis and Search for Antitumor Preparations" (in Russian). Iss. 2. M. 1967. pp. 75-81; Giller S. A. et al. In the book "Furozolidine". (in Russian). Riga, 1962. pp. 5-18; Duavarte A. Zh., Zidermane A. A., Kravchenko I. M. et al. In the book "Proceedings of the 1st All-Union Conference on Chemotherapy of Malignant Tumors." Riga. 1968. pp. 216-217; Duavarte A. Zh. et al. In the book "Antitumor Compounds of the 5-nitrofuran Series." (in Russian). Riga, 1972. pp. 17-30)] and 5-aminobenzimidazol [Fuska J., Fuskova A., Jurasek A. "Neoplasma (Bratisl.)". 1973. v. 20. pp. 171-179].
In the search for new antitumor preparations nitrofuran derivatives containing alkylating groups, such as N,N-bis (2-chloroethyl)hydrazide, N,N-bis(2-chloroethyl)hydrazine and N,N-bis(2-chloroethyl)amide have been synthesized [Giller S. A. et al. In the book "Methods of Synthesis and Search for Antitumor Preparations" (in Russian). Iss. 2. M., 1967. pp. 75-81; Duavarte A. Zh., Zidermane A. A. et al. In the book "Proceedings of the 1st All-Union Conference on Chemotherapy of Malignant Tumors" (in Russian). Riga. 1968. pp. 264-265; 266; Duavarte A. Zh. In the book "Antitumor Compounds of the 5-nitrofuran Series." (in Russian). Riga. 1972. pp. 33-44]. Beginning with 1964, synthesis and studies of biological properties of nitrofurylpolyenyl heterocycles were conducted, that is compounds of a new structural type were studies, and the positive result was due to a combination of nitrofuran and heterocycle in one molecule by using a system of --CH.dbd.CH-- bonds (USSR Inventor's Certificate No. 333835). Nitrofurylvinyl pyrimidines are most active among the compounds of this vlass Katae H., Iwana H., Takase Y. et al.- "Arzneimittel-Forsch.", 1967, Bd. 17.s. 1030-1034; Kravchanko I. M. Zidermane A. A. et al. in the book "Proceedings of the 1st All-Union Conference on Chemotherapy of Malignant Tumors. Riga". 1968. pp. 234-235 and also quinolines Zidermane A. A. et al. "Fharmacology and Toxicology". 1970. No. 6. pp. 711-715; Miura K., Ikeda M., Oohashi T. et al. - "J. pharm. Soc. Jap.". 1964. v. 84. pp. 341-345; Ujiie T.-"Chem. pharm. Bull." 1966. v. 14. pp. 461-466; Miura K. et al. - "J. pharm. Soc. Jap.". 1964. v. 84. pp. 537-543; Miura K., Okda I. "Chem. pharm. Bull.". 1965. v. 13, pp. 525-528.
A known 2-[2'-(5"-nitrofuryl-2")vinyl]quinoline-4-carboxylic acid amide prepared by condensation reaction of 2-methyl-quinoline-4-carboxylic acid amide with 5-nitrofurfural exhibits a very narrow range of antitumoral activity [K. Miura, M. Ikeda, T. Oohashi, Y. Igarashi. "J. Pharm. Soc. Japan." 1964, 84(6). pp. 537-543; K. Miura, I. Okada. "Chem. Pharm. Bull." 1965. 13 (15). pp. 525-528]. We have not found any antitumor activity for Jensen sarcoma, Pliss lymphosarcoma and Walker carcinosarcoma with peroral administration of 2-[2'-(5"-nitrofuryl-2")vinyl] quinoline-4-carboxylic acid amide.
As far as the biochemical mechanism of antitumoral activity of non-alkylating 5-nitrofurans is concerned, including nitrofurylvinyl- and nitrofurylbutadiene quinolines, we have found that these compounds decelerate respiration associated with phosphorylation, and some nitrofurylvinyl quinolines inhibit the activity of dehydrogeneses of ascitic cells of Ehrlich tumor, biosynthesis of DNA, RNA and proteins.
All above-described 5-nitrofuran derivatives have not found any practical application in the medicine so far in view of toxicity, low selectivity of antiblastic activity and poor solubility.